This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The tyrosine phosphatase PTP-1B is a regulator of insulin signaling and glucose homeostasis and inhibitors of this enzyme would be useful new therapeutics for the treatment of diabetes and its complications. Here we propose structure-based design of PTP-1B inhibitors using breakaway tethering to target both the active site and a recently discovered novel allosteric site. We need access to the synchrotron to generate the high quality diffraction data required to support drug design of inhibitors of the active and allosteric sites since we have only been able to achieve medium to low resolution data sets in-house. In addition, use of the synchrotron would facilitate what has been up to now an elusive objective, a crystal structure of the full-length PTP-1B.